Oxidative Cysteine Modification of Thiol Isomerases in Thrombotic Disease: A Hypothesis

Oxidative stress is a characteristic of many systemic diseases associated with thrombosis. Thiol isomerases are a family of oxidoreductases important in protein folding and are exquisitely sensitive to the redox environment. They are essential for thrombus formation and represent a previously unrecognized layer of control of the thrombotic process. Yet, the mechanisms by which thiol isomerases function in thrombus formation are unknown. The oxidoreductase activity of thiol isomerases in thrombus formation is controlled by the redox environment via oxidative changes to active site cysteines. Specific alterations can now be detected owing to advances in the chemical biology of oxidative cysteine modifications. Understanding of the role of thiol isomerases in thrombus formation has focused largely on identifying single disulfide bond modifications in isolated proteins (e.g., α_IIbβ₃, tissue factor, vitronectin, or glycoprotein Ibα [GPIbα]). An alternative approach is to conceptualize thiol isomerases as effectors in redox signaling pathways that control thrombotic potential by modifying substrate networks. Cysteine-based chemical biology will be employed to study thiol-dependent dynamics mediated by the redox state of thiol isomerases at the systems level. This approach could identify thiol isomerase-dependent modifications of the disulfide landscape that are prothrombotic.